The long term goal of this project is to understand the role of corticosteroids (CORT) in the viability of hippocampal neurons. Normal aging, stress, and prolonged illness produce CORT hypersecretion, which has been associated with increased oxidative damage to neurons, hippocampal neuron loss, and cognitive impairment. Conversely, there is evidence that low levels of CORT are required for the survival of hippocampal granule cells and pyramidal cells. The high affinity, low capacity mineralocorticoid receptor (MR) and the low affinity, high capacity glucocorticoid receptor (GR) mediate CORT effects. The specific aims of this proposal address the hypothesis that MR mediates neuroprotective effects of CORT, while CORT action through GR renders neurons more susceptible to potentially toxic challenges. Specific Aim 1 tests this hypothesis directly by quantitating neuronal death in primary fetal hippocampal cultures treated chronically with MR and GR agonists/antagonists prior to glutamate, staurosporine or inflammatory cytokine challenge. Specific Aim 2 will test the hypothesis at altered neuronal viability correlates with MR- and GR-associated changes in the expression of neuroprotective and/or death-promoting gene products and transcription factor availability. Specific Aim 3 will test the hypothesis that MR and GR differentially affect neuronal ability to withstand insults by promoting and disrupting, respectively, mitochondrial integrity.